Abstract
BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries. NAFLD encompasses a spectrum of diseases, ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and liver failure. The etiology of NAFLD remains unclear but is thought to relate to increased fatty acid flux within the liver that results in toxic fatty acid metabolite production. One source of increased fatty acid flux is fructose/sucrose-induced hepatic lipogenesis. Current treatment for NAFLD encompasses dietary modifications. However, little scientific evidence exists on which to base many dietary recommendations, especially the intake of different types of carbohydrates and fats. We hypothesized that lipid mixtures of unsaturated fatty acids would inhibit lipogenesis and subsequent hepatic steatosis induced by high carbohydrate diets. The aim of this study was to examine the effects of different complex mixtures of fatty acids upon the development of fructose/sucrose-induced hepatic steatosis.MethodsC57BL/6 mice were randomized to normocaloric chow-based diets that varied in the type of carbohydrate (starch, sucrose, fructose). Animals in each carbohydrate group were further randomized to diets that varied in lipid type (no additional lipid, soybean oil, fish oil, olive/soybean oil, macadamia nut oil). These oils were chosen based upon their content of omega-6 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, omega-9 monounsaturated fatty acids, or omega-7 monounsaturated fatty acids. Fatty acid flux in the liver was determine by assessing hepatic lipid content (steatosis). We also assessed fatty acid levels in the plasma and liver of the animals, hepatic lipogenesis activity, hepatic stearoyl-CoA-1 desaturase activity, and hepatic elongase activity.ResultsAnimals consumed similar amounts of the diets and maintained normal body weights throughout the study. Both sucrose and fructose induced hepatic lipogenesis and steatosis, with fructose being more potent. All mixed lipids similarly inhibited steatosis, limiting lipid content to levels found in the control (starch) animals. Lipogenesis and stearoyl-CoA-1 desaturase activity were increased in the sucrose and fructose groups. Levels of these enzymatic processes remained at baseline in all of the lipid groups.ConclusionThis is the first study to compare various complex lipid mixtures, based upon dietary oils with different types of long-chain fatty acids, upon development of sucrose/fructose-induced steatosis. Both carbohydrate source and lipid content appear important for the modulation of steatosis. Moderate intake of complex lipids with high unsaturated to saturated fatty acid ratios inhibited both lipogenesis and steatosis.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries
NAFLD encompasses a spectrum of diseases that includes steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma [1, 3, 4]
It is postulated that excess free fatty acid (FFA) traffic within hepatocytes that accompanies the development of steatosis leads to the generation of toxic lipid metabolites, which increase oxidative stress and inflammation, resulting in hepatocyte injury that leads to cirrhosis and liver failure [7, 9]
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries. NAFLD encompasses a spectrum of diseases, ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and liver failure. It is postulated that excess free fatty acid (FFA) traffic (from diet, de novo lipogenesis, adipose lipolysis, impaired lipid oxidation) within hepatocytes that accompanies the development of steatosis leads to the generation of toxic lipid metabolites (i.e., acyl-CoA, lysophosphatidylcholine, ceramides, phosphatidic acid), which increase oxidative stress and inflammation (i.e., induction of NFκB, IL-6, IL-1, TNF-alpha), resulting in hepatocyte injury that leads to cirrhosis and liver failure [7, 9]. Increased fatty acid flux and triglyceride formation results largely from an increased supply of fatty acids (i.e., from lipolysis and diet) and de novo lipogenesis [10,11,12] Both processes are increased in patients with NAFLD [10,11,12] and play important roles in lipid accumulation. Inhibition of hepatic steatosis (i.e., free fatty acid flux) has been shown to prevent progression of steatosis to NASH/cirrhosis [13,14,15]
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